Using methods of clinical opthalmology and experimental pathology, we propose to study the abnormalities of the blood-retinal barrier in the hereditary diabetic rodents, the streptozotocin diabetic rodents, the spontaneously diabetic dogs, and the alloxan diabetic dogs. 1. Specifically, we shall perform (a) standard light and electron microscopic studies, (b) freeze-dried fluorescence microscopy after injection of fluorescent dyes, and (c) electron microscopic tracer study on hereditary diabetic and streptozotocin diabetic rodents and correlate them with vitreous fluorophotometric measurements. 2. We will determine the anatomic site of breakdown of blood-retinal barrier and the time of onset relative to the duration of hereditary or chemically-induced diabetes in rodents. We will grade the severity of the barrier breakdown with respect to the molecular size of the leaked tracers. 3. We will determine the ultrastructural alteration of the blood-retinal barrier induced by hyperosmotic intra-arterial infusion in normal rodents and compare that seen in diabetic rodents. We will examine if the blood-retinal barrier becomes fragile prior to actual breakdown in rodents with early hereditary diabetes by hyperosmotic infusion. 4. We will determine the alteration of the retinal mean circulation time in spontaneously diabetic and alloxan diabetic dogs, and compare with the vitreous fluorophotometric readings of these animals. The effect of hyperosmotic infusion on the retinal mean circulation time of these animals will also be studied. The ultimate goal of this proposal is to characterize the pathogenetic mechanisms of the disturbance of the blood-retinal barrier in diabetic animals and relate them to the findings of vitreous fluorophotometric and retinal mean circulation time.